Phase I Study of Oral Azacitidine in Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia

Garcia‐Manero, Guillermo; Gore, Steven D.; Cogle, Christopher R.; Ward, Renee; Shi, Tao; MacBeth, Kyle J.; Laille, Eric; Giordano, Heidi; Sakoian, Sarah; Jabbour, Elias; Kantarjian, Hagop M.; Skikne, Barry S.

doi:10.1200/jco.2010.34.4226

Cited by 231 publications

(239 citation statements)

References 15 publications

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“…CC‐486, is an oral drug formulation of azacitidine. Oral administration of CC‐486 is not pharmacokinetically equivalent to parenteral azacitidine, and thus can induce alternate demethylated regions in the genome 24. This is thought to account for responses in both azacitidine naïve and azacitidine failure patients 24, 26.…”

Section: Discussionmentioning

confidence: 99%

“…Oral administration of CC‐486 is not pharmacokinetically equivalent to parenteral azacitidine, and thus can induce alternate demethylated regions in the genome 24. This is thought to account for responses in both azacitidine naïve and azacitidine failure patients 24, 26. In addition, there is considerable flexibility in dosing and schedule with an oral DNMTi, so understanding the safety profile and pharmacodynamics of CC‐486 in various treatment regimens may provide new treatment strategies for patients with myeloid malignancies.…”

Section: Discussionmentioning

confidence: 99%

“…A phase 1 dose‐escalation study evaluated treatment outcomes for patients with MDS, CMML, or AML who, after receiving an initial cycle of standard subcutaneous (SC) azacitidine dosing (75 mg/m 2 /day for 7 days of a 28‐day cycle), received CC‐486 doses of 180‐600 mg/day for 7 consecutive days per cycle thereafter 24. Pharmacodynamic evaluation of 7‐day administration of SC azacitidine and oral CC‐486 showed both treatments resulted in greatest respective reductions in global methylation (per Infinium Human Methylation27 BeadArray assay; Illumina, San Diego, CA) near mid‐cycle, after which, methylation levels began to rise to approximately pretreatment levels 24, 25. As some of the benefit of parenteral azacitidine is thought to be from global hypomethylation, it is reasonable to consider that prolongation of hypomethylation may be beneficial.…”

Section: Introductionmentioning

confidence: 99%

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Extended dosing with CC‐486 (oral azacitidine) in patients with myeloid malignancies

Savona

Kolibaba²,

Conkling

et al. 2018

American J Hematol

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CC‐486 (oral azacitidine) is an epigenetic modifier in clinical development for treatment of hematological cancers. This study of extended CC‐486 dosing included patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). After a pharmacokinetic assessment period, 31 patients (MDS n = 18, CMML n = 4, and AML n = 9) entered a clinical phase in which they received CC‐486 300 mg once‐daily for 21 days of repeated 28‐day cycles. Median age was 71 years (range: 53‐93); 42% of patients were aged ≥75 years. A total of 5 patients with AML (63%) had prior MDS. Median number of CC‐486 treatment cycles was 4 (range: 1‐32). The most common treatment‐emergent adverse events (TEAEs) were gastrointestinal (84% of patients) and hematologic (81%). Most common grade 3‐4 TEAEs were neutropenia (n = 13, 42%) and anemia (n = 9, 29%). Ten patients experienced grade 4 neutropenia. Infrequently, CC‐486 dose was interrupted or reduced due to gastrointestinal (n = 5, 16%) or hematologic (n = 6, 19%) TEAEs. Overall response rate (complete remission [CR], CR with incomplete hematological recovery [CRi], partial remission [PR], marrow CR) in the MDS/CMML subgroups was 32% and in the AML subgroup (CR/CRi/PR) was 22%. Red blood cell transfusion independence rates in the MDS/CMML and AML subgroups were 33% and 25%, respectively, and 2 MDS/CMML patients attained hematologic improvement as a best response on‐study. No baseline gene mutation was predictive of response/nonresponse. CC‐486 allows flexible dosing and schedules to improve tolerability or response. Neutropenia in early treatment cycles deserves scrutiny and may warrant initiation of prophylactic antibiotics.KEY POINTSThe safety profile of oral CC‐486 was comparable to that of injectable azacitidine; most adverse events were hematological and gastrointestinal.Extended (21‐day/cycle) CC‐486 dosing induced responses in patients with hematological malignancies, many of whom had prior DNMTi failure.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Extended dosing with CC‐486 (oral azacitidine) in patients with myeloid malignancies

Savona

Kolibaba²,

Conkling

et al. 2018

American J Hematol

Self Cite

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“…AZA PH US 2007 CL 005 was a phase I open-label dose-escalation study that evaluated the safety, PK, and pharmacodynamics (PD) of oral azacitidine in patients with MDS, CMML, or AML [66]. This trial had two parts (Fig.…”

Section: Dose-finding Study Of Oral Azacitidinementioning

confidence: 99%

“…This trial had two parts (Fig. 2) [57,66]: In part 1, 41 patients (71% MDS, 10% CMML, 20% AML) received 7-day dosing of s.c. azacitidine for a single 28-day cycle, followed by oral azacitidine for 7 days of 28-day cycles (cycles 2 and beyond; Table 1). During cycles 1 and 2, PK (days 1 and 7) and PD (days 1, 3, 8, 15, 22, and 28) profiles were assessed.…”

Section: Dose-finding Study Of Oral Azacitidinementioning

confidence: 99%

Oral Azacitidine (CC-486) for the Treatment of Myelodysplastic Syndromes and Acute Myeloid Leukemia

Cogle

Scott

Boyd³

2015

The Oncologist

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The myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal myeloid malignancies characterized by multilineage cytopenias, recurrent cytogenetic abnormalities, and risk of progression to acute myeloid leukemia (AML). AML, which can occur de novo as well as secondary to MDS, is characterized by malignant clones of myeloid lineage in the bone marrow and peripheral blood, with dissemination into tissues. The cytidine nucleoside analog and epigenetic modifier azacitidine is approved in the U.S. for the treatment of all French-American-British subtypes of MDS and in many countries for the treatment of AML with 20%-30% blasts and multilineage dysplasia according to the World Health Organization classification. Benefits of azacitidine treatment of patients with AML with .30% blasts have also been shown in a recent phase III trial. Oral administration of azacitidine may enhance patient convenience, eliminate injection-site reactions, allow for alternative dosing and scheduling, and enable long-term treatment. Phase I studies with oral azacitidine (CC-486) have shown biological activity, clinical responses, and tolerability in patients with MDS and AML. Extended dosing schedules of oral azacitidine (for 14 or 21 days of 28-day cycles) are currently under investigation as frontline therapy in patients with lower risk MDS, as maintenance therapy for patients with AML not eligible for stem cell transplant, and as maintenance therapy for patients with MDS or AML following stem cell transplant. This review presents clinical data supporting the use of injectable azacitidine in MDS and AML and examines the rationale for and results of the clinical development of oral azacitidine.

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Contemporary Management of Acute Myeloid Leukemia

Venugopal,

Sekeres

2024

JAMA Oncol

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ImportanceAcute myeloid leukemia (AML) is a clonal hematopoietic cancer that disrupts normal hematopoiesis, ultimately leading to bone marrow failure and death. The annual incidence rate of AML is 4.1 per 100 000 people in the US and is higher in patients older than 65 years. Acute myeloid leukemia includes numerous subgroups with heterogeneous molecular profiles, treatment response, and prognosis. This review discusses the evidence supporting frontline therapies in AML, the major principles that guide therapy, and progress with molecularly targeted therapy.ObservationsAcute myeloid leukemia is a genetically complex, dynamic disease. The most commonly altered genes include FLT3, NPM1, DNMT3A, IDH1, IDH2, TET2, RUNX1, NRAS, and TP53. The incidence of these alterations varies by patient age, history of antecedent hematologic cancer, and previous exposure to chemotherapy and/or radiotherapy for any cancer. Since 2010, molecular data have been incorporated into AML prognostication, gradually leading to incorporation of targeted therapies into the initial treatment approach of induction chemotherapy and subsequent management. The first molecularly targeted inhibitor, midostaurin, was approved to treat patients with AML with FLT3 variants in 2017. Since then, the understanding of the molecular pathogenesis of AML has expanded, allowing the identification of additional potential targets for drug therapy, treatment incorporation of molecularly targeted therapies (midostaurin, gilteritinib, and quizartinib targeting FLT3 variants; ivosidenib and olutasidenib targeting IDH1 variants, and enasidenib targeting IDH2), and identification of rational combination regimens. The approval of hypomethylating agents combined with venetoclax has revolutionized the therapy of AML in older adults, extending survival over monotherapy. Additionally, patients are now referred for hematopoietic cell transplant on a more rational basis.Conclusions and RelevanceIn the era of genomic medicine, AML treatment is customized to the patient’s comorbidities and AML genomic profile.

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Phase I Study of Oral Azacitidine in Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia

Cited by 231 publications

References 15 publications

Extended dosing with CC‐486 (oral azacitidine) in patients with myeloid malignancies

Extended dosing with CC‐486 (oral azacitidine) in patients with myeloid malignancies

Oral Azacitidine (CC-486) for the Treatment of Myelodysplastic Syndromes and Acute Myeloid Leukemia

Contemporary Management of Acute Myeloid Leukemia

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